Phenylimidazolidines containing nitrooxy or carbonyloxy groups

ABSTRACT

A subject of the invention is the products of formula (I):                    
     in which: 
     R 1  and R 2  represent in particular cyano and trifluoromethyl, 
     R 3  represents in particular alkyl, alkenyl or alkynyl, substituted in particular by nitrooxy or carbonyloxy, 
     R 4  and R 5  represent in particular methyl optionally substituted by fluorine, 
     X and Y represent in particular oxygen, as well as their salts and isomers.

This application is a 371 of PCT/FR96/02029 filed Dec. 19, 1996.

The present invention relates to new phenylimidazolidines containing inparticular a nitrooxy or carbonyloxy radical, their preparation process,the new intermediates obtained, their use as medicaments, their new useand the pharmaceutical compositions containing them.

A subject of the present invention is the products of formula (I):

in which:

R₁ and R₂, identical or different, are chosen from cyano, nitro,trifluoromethyl radicals and halogen atoms,

R₃ represents a linear or branched aryl, arylalkyl, alkyl, alkenyl oralkynyl radical containing at most 10 carbon atoms substituted by aradical chosen from the following radicals: nitrooxy, alkoxycarbonyloxy,cycloalkoxycarbonyloxy, carboxyalkoxy, hydroxyacyl, hydroxyacyloxy,alkoxyacyl and alkoxyacyloxy, in which the alkyl, alkoxy, acyl andacyloxy radicals are linear or branched, containing at most 10 carbonatoms, the cycloalkoxy radical contains 3 to 7 members, the carboxyradical is free, salified, esterified or amidified and the hydroxyradical is free, esterified, etherified or protected,

R₄ and R₅ are either identical or different and represent a linear orbranched alkyl radical containing at most 4 carbon atoms and optionallysubstituted by a halogen atom, or form with the carbon atom to whichthey are linked a cyclic radical constituted by 3 to 7 members andoptionally containing one or more identical or different heteroatoms,chosen from oxygen, sulphur or nitrogen atoms,

X and Y, identical or different, represent an oxygen or sulphur atom,said products of formula (I) being in all the possible racemic,enantiomeric and diastereoisomeric isomer forms, as well as the additionsalts with mineral and organic acids or with mineral and organic basesof said products of formula (I).

In the products of formula (I) and in what follows:

the term halogen designates the fluorine, chlorine, bromine or iodineatoms.

The fluorine, chlorine or bromine atoms are preferred.

The term linear or branched alkyl radical designates the followingradicals: methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,tert-butyl, pentyl, isopentyl, hexyl, isohexyl and also heptyl, octyl,nonyl and decyl as well as their linear or branched position isomers.

The alkyl radicals having at most 6 carbon atoms are preferred and inparticular the methyl, ethyl, propyl, isopropyl, n-butyl, n-pentyl andn-hexyl radicals,

the term linear or branched alkenyl radical designates the vinyl, allyl,1-propenyl, butenyl, 1-butenyl, pentenyl or hexenyl radical as well astheir linear or branched position isomers.

Among the alkenyl radicals, the vinyl, allyl, n-butenyl or isobutenylvalues are preferred,

the term alkynyl designates a linear or branched radical having at most12 and preferably 4 carbon atoms such as for example ethynyl, propargyl,butynyl, pentynyl or hexynyl.

Among the alkynyl radicals, the propargyl radical is preferred.

The term linear or branched alkoxy radical designates the followingradicals: methoxy, ethoxy, propoxy, isopropoxy, linear, secondary ortertiary butoxy, pentoxy or hexoxy as well as their linear or branchedposition isomers,

the term cyclic radical constituted by 3 to 7 members and optionallycontaining one or more identical or different heteroatoms, chosen fromoxygen, sulphur or nitrogen atoms, designates on the one hand acycloalkyl radical which itself designates in particular the cyclobutyl,cyclopentyl and cyclohexyl radicals and on the other hand a carbocyclicradical interrupted by one or more heteroatoms chosen from oxygen,nitrogen or sulphur atoms such as quite particularly the saturatedmonocyclic heterocyclic radicals. The following radicals can bementioned for example: oxetannyl, oxolannyl, dioxanyl, dithiolane,thiooxolane, thiooxane, pyrrolidinyl, piperidyl, piperazinyl,morpholinyl, azetidine, oxetane and thietane, and there can be indicatedquite particularly:

the rings with 4 members containing at most 1 heteroatom, such as:

the rings with 5 members containing at most 1 heteroatom, such as:

the rings with 6 members containing at most 6 heteroatoms, such as:

The following radical can also be indicated:

in which W represents an alkyl or aryl radical as defined above,

the term cycloalkoxy radical represents in particular the cyclobutoxy,cyclopentoxy or cyclohexyloxy radicals,

the term acyl radical preferably designates the formyl, acetyl,propionyl, butyryl and benzoyl radicals, but also the valeryl, hexanoyl,acryloyl, crotonoyl and carbamoyl radicals,

the term acyloxy radical designates the radicals in whichthe acylradicals have the meaning indicated above and for example the acetoxy orpropionyloxy radicals,

the term aryl designates the carbocyclic aryl radicals such as phenyl ornaphthyl and the monocyclic heterocyclic aryl radicals with 5 or 6members or constituted by condensed rings, containing one or moreheteroatoms preferably chosen from oxygen, sulphur and nitrogen. Amongthe heterocyclic aryls with 5 members, the following radicals can bementioned: furyl, thienyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl,thiadiazolyl, pyrazolyl, isoxazolyl, tetrazolyl.

Among the heterocyclic aryls with 6 members, the pyridyl, pyrimidinyl,pyridazinyl, pyrazinyl radicals can be mentioned.

Among the condensed aryl radicals, the indolyl, benzofurannyl,benzothienyl, quinolinyl radicals can be mentioned. The phenyl,tetrazolyl and pyridyl radicals are preferred.

The term arylalkyl designates the radicals resulting from thecombination of the alkyl radicals and the aryl radicals mentioned above.

The benzyl, phenylethyl, pyridylmethyl, pyridylethyl or tetrazolylmethylradicals are preferred.

the terms alkoxy- and cycloalkoxy-carbonyloxy, carboxyalkoxy, hydroxy-and alkoxy-acyl and -acyloxy, represent the radicals in which thealkoxy, acyl and acyloxy radicals have the meanings indicated above:there can be mentioned for example and in a non-expaustive manner, thefollowing radicals: isopropyloxycarbonyloxy, cyclopentyloxycarbonyloxy,cyclohexyloxycarbonyloxy, methoxycarbonyloxy, carboxybutyl,ethoxycarbonylbutyl, hydroxyacetyl, hydroxypropionyl or methoxybutyryl;hydroxyacetoxy or hydroxypropionyloxy; methoxy- or ethoxypropionyloxy.

By way of example and in a non-exhaustive manner, in addition to thevalues indicated above and to those given hereafter, in particular inthe experimental part, R₃ can therefore in particular represent theisopropyloxy- or cyclohexyloxy or cyclopentyloxy -carbonyloxybutyl orthe corresponding radicals in which the isopropyloxy remainder and thebutyl remainder take the other values of the alkoxy and alkyl radicalsmentioned above respectively such as, for example, pentoxy, butoxy,ethoxy, pentyl or isopropyl; such alkyl radicals can also be replaced byalkenyl or alkynyl remainders such as for example pentenyl, butenyl,propenyl, pentynyl, butynyl or allyl or also by aryl or arylalkylremainders as defined above, such as, for example, phenyl, pyridyl,benzyl, phenethyl, pyridylmethyl or pyridylethyl. R₃ can also representfor example the following radicals: hydroxymethylcarbonylethyl,hydroxymethylcarbonylmethyl, hydroxy-1-difluoro-2,2-butyl,hydroxy-l-difluoro-2,2-propyl, hydroxyphenylmethyl,dihydroxyphenylmethyl, hydroxyphenyl or also hydroxymethylphenyl.

As particular examples of an alkyl radical substituted by a halogenatom, there can be mentioned the mono-fluoro-, chloro- or bromo-methyl,ethyl and -isopropyl radicals.

The carboxy radical or radicals of the products of formula (I) can befree, salified, esterified or amidified by various groups known to a manskilled in the art, amongst which there can be mentioned, for example:

among the salification compounds, mineral bases such as, for example, anequivalent of sodium, potassium, lithium, calcium, magnesium or ammoniumor organic bases such as, for example, methylamine, propylamine,trimethylamine, diethylamine, triethylamine, N,N-dimethylethanolamine,tris (hydroxymethyl) amino methane, ethanolamine, pyridine, picoline,dicyclohexylamine, morpholine, benzylamine, procaine, lysine, arginine,histidine, N-methylglucamine.

The sodium or potassium salts are preferred.

Among the esterification compounds, the alkyl radicals in order to formalkoxy carbonyl groups such as, for example, methoxycarbonyl,ethoxycarbonyl, propoxycarbonyl, butoxy-, isobutoxy- andtert-butoxy-carbonyl or benzyloxycarbonyl, these alkyl radicals beingable to be substituted by radicals chosen for example from halogenatoms, hydroxyl, alkoxy, acyl, acyloxy, alkylthio, amino or arylradicals such as, for example, in the following groups: chloromethyl,hydroxypropyl, methoxymethyl, propionyloxymethyl, methylthiomethyl,dimethylaminoethyl, benzyl or phenethyl.

Radicals formed with the easily cleavable ester remainders can also bementioned such as the methoxymethyl, ethoxymethyl radicals; theacyloxyalkyl radicals such as pivaloyloxymethyl, pivaloyloxyethyl,acetoxymethyl or acetoxyethyl; the alkyloxycarbonyloxy alkyl radicalssuch as the methoxycarbonyloxy methyl or ethyl radicals, theisopropyloxycarbonyl methyl or ethyl radicals.

A list of such ester radicals can be found for example in the EuropeanPatent EP 0,034,536.

By amidified carboxy is meant the groups of —CON(R₆)(R₇) type in whichthe R6 and R₇ radicals, identical or different, represent a hydrogenatom or an alkyl radical having 1 to 4 carbon atoms such as the methyl,ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butylradicals.

Among the —CON(R₆)(R₇) groups defined above, those in which the—N(R₆)(R₇) radical represents the amino, mono or dimethylamino radicalare preferred.

The N(R₆)(R₇) radical can also represent a heterocycle which may or maynot contain an additional heteroatom. The pyrrolyl, imidazolyl, indolyl,piperidinyl, morpholinyl, piperazinyl radicals can be mentioned. Thepiperidino or morpholino radicals are preferred.

Examples of the protective group of the protected hydroxyl radical aregiven in particular in the usual book of a man skilled in the art:Protective Groups in Organic Synthesis, Theodora W. Greene, HarvardUniversity, published in 1981 by Wiley-Interscience Publishers, JohnWiley & Sons.

The addition salts with mineral or organic acids of the products offormula (I) can be, for example, the salts formed with the followingacids: hydrochloric, hydrobromic, hydroiodic, nitric, sulphuric,phosphoric, propionic, acetic, formic, benzoic, maleic, fumaric,succinic, tartaric, citric, oxalic, glyoxylic, aspartic, ascorbic,alkylmonosulphonic such as for example methanesulphonic,ethanesulphonic, propanesulphonic, alkyldisulphonic such as for examplemethanedisulphonic, alpha, beta-ethanedisulphonic, arylmonosulphonicsuch as benzenesulphonic, metasulphobenzoic and aryldisulphonic.

There can be mentioned more particularly the salts formed withhydrochloric or methanesulphonic acids for example.

It may be remembered that stereoisomerism can be defined as theisomerism of compounds having the same developed formulae, but thedifferent groups of which are arranged differently in space, such as inparticular in the boat and chair shapes of the cyclohexane andmono-substituted cyclohexanes whose substituent can be in the axial orequatorial position, and the different possible rotational conformationsof ethane derivatives. However, another type of stereoisomerism exists,due to the different spatial arrangements of substituents fixed eitheron bond doubles, or on rings, which is often called geometricalisomerism or cistrans isomerism. The term stereoisomeric is used in thepresent Application in its broadest sense and therefore relates to allof the compounds indicated above.

In the products of formula (I) and in what follows, it can be notedthat:

the hydrogen atoms which are contained by the optionally substitutedalkyl or alkenyl radicals that R₃ can represent, can be deuterium atoms,

the fluorine atoms which can be represented by the halogen atoms, can bean ¹⁸F atom useful for the medical imagery. R₃ thus represents inparticular a linear or branched phenyl, pyridyl, benzyl, phenethyl,pyridylalkyl, alkyl, alkenyl or alkynyl radical, containing at most 10carbon atoms, and substituted by a radical chosen from the followingradicals:

with R₆ representing a hydrogen atom, a linear or branched alkyl or acylradical containing at most 6 carbon atoms or a cycloalkyl radicalcontaining 3 to 7 members, and R₇ and R₈, identical or different,representing a linear or branched alkyl or acyl radical containing atmost 6 carbon atoms.

Thus a subject of the present invention is the products of formula (I)as defined above, in which:

R₁ and R₂ either both represent a chlorine atom, or are identical ordifferent and are chosen from cyano, nitro and trifluoromethyl radicals,

R₃ represents a linear or branched phenyl, pyridyl, phenylalkyl,pyridylalkyl, alkyl, alkenyl or alkynyl radical containing at most 6carbon atoms, substituted by a radical chosen from the followingradicals: nitrooxy, hydroxyacyl, alkoxy-, acyloxy- andcycloalkoxy-carbonyloxy, in which radicals, if appropriate, the acyl,acyloxy and alkoxy radicals are linear or branched, containing at most 6carbon atoms and the hydroxyl radical is free, esterified or protected,

R₄ and R₅ are either identical or different and represent a methylradical optionally substituted by a halogen atom, or form with thecarbon atom to which they are linked a cyclobutyl, cyclopentyl,cyclohexyl, dioxanyl radical or a

radical in which W represents an oxygen, sulphur or —NH radical,

X and Y, identical or different, represent an oxygen or sulphur atom,

said products of formula (I) being in all the possible racemic,enantiomeric and diastereoisomeric isomer forms, as well as the additionsalts with mineral and organic acids or with mineral and organic basesof said products of formula (I).

The

radical represents in particular the piperidyl or tetrahydropyrannylradical.

A particular subject of the present invention is the products of formula(I) as defined above, in which:

R₁ and R₂ represent a cyano radical and a trifluoromethyl radical,

R₃ represents a linear or branched alkyl, alkenyl or alkynyl radicalcontaining at most 4 carbon atoms substituted by a radical chosen fromthe nitrooxy and

radicals in which R₉ represents a linear or branched alkyl radicalcontaining at most 4 carbon atoms or a cycloalkyl radical containing 5or 6 members,

R₄ and R₅ are either identical or different and represent a methylradical optionally substituted by a fluorine atom, or form with thecarbon atom to which they are attached a cyclohexyl radical

X and Y represent an oxygen atom, said products of formula (I) being inall the possible racemic, enantiomeric and diastereoisomeric isomerforms, as well as the addition salts with mineral and organic acids orwith mineral and organic bases of said products of formula (I).

A particular subject of the present invention is the products of formula(I) as defined above in which R₄ and R₅ represent a methyl radical andR₁, R₂, R₃, X and Y have the meanings indicated above.

Among the preferred products of the invention, there can be mentionedmore particularly the products of formula (I) as defined above the namesof which follow:

4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-2,4-dioxo-1-imidazolidinyl)butyl and 1-methylethylcarbonate,

4-(4,4-dimethyl-2,5-dioxo-3-(4-nitrooxybutyl)-1-imidazolidinyl)-2-(trifluoromethyl)benzonitrile, said products of formula (I) being in all the possibleracemic, enantiomeric and diastereoisomeric isomer forms, as well as theaddition salts with mineral and organic acids or with mineral andorganic bases of said products of formula (I).

A subject of the present invention is also a preparation process for theproducts of formula (I), as defined above, characterized in that:

either, in the presence of a tertiary base, a product of formula (II):

in which R′₁ and R′₂ have the meanings indicated above for R₁ and R₂respectively, in which the optional reactive functions are optionallyprotected and X has the meaning indicated above, is reacted with aproduct of formula (III):

in which R₄ and R₅ have the meanings indicated above, and R′₃ has themeaning indicated above for R₃, in which the optional reactive functionsare optionally protected, in order to obtain a product of formula (IV):

in which X, R′₁, R′₂, R′₃, R₄ and R₅ have the meanings indicated above,

which is converted into a product of formula (V):

in which X, R′₁, R′₂, R′₃, R₄ and R₅ have the meanings indicated above,

or a product of formula (VI):

in which R′₁, R′₂, R₄ and R₅ have the meanings indicated above, isreacted with a reagent of formula Hal-R′₃ in which R′₃ has the meaningindicated above, and Hal represents a halogen atom, in order to obtainthe corresponding products of formula (V) as defined above in which Xrepresents an oxygen atom,

or is reacted on a product of formula (VII):

in which R′₁, R′₂, R₄, R₅ and X have the meanings indicated above,

and Rx represents a linear or branched aryl, arylalkyl, alkyl, alkenylor alkynyl radical containing at most 10 carbon atoms, which issubjected:

either to the action of a compound of formula (VIII):

in which Hal represents a halogen atom and Ry represents a radicalchosen from alkoxy, cycloalkoxy, hydroxyalkyl or alkoxyalkyl radicals,as defined above, in order to obtain a product of formula (IX):

in which R′₁, R′₂, R₄, R₅, X, Rx and Ry have the meanings indicatedabove,

or to a halogenation reaction in order to obtain a product of formula(X):

in which R′₁, R′₂, R₄, R₅, X, Rx and Hal have the meanings indicatedabove,

which is subjected to the action of silver nitrate in order to obtainthe product of formula (XI):

in which R′₁, R′₂, R₄, R₅, X, Rx and Hal have the meanings indicatedabove,

which products of formulae (IV), (V), (IX) and (XI), if necessary or ifdesired, in order to obtain products of formula (I) as defined in claim1, can be subjected to any one or more of the following reactions, inany order:

a) if appropriate conversion of the >C═S group which can be representedby >C═X into the >C═O group,

b) release of the OH radical which can be carried by R′₃,

c) esterification or etherification reaction of the OH radical which canbe carried by R₃,

d) elimination reaction of the optional protective groups,

e) if appropriate the action of an esterification, amidification orsalification agent,

f) resolution reaction of the racemic forms, said products of formula(I) thus obtained being in all the possible racemic, enantiomeric anddiastereoisomeric isomer forms.

The action of the products of formula (II) with the products of formula(III) to obtain the products of formula (IV) can be carried out in thepresence of methylene chloride, at a temperature of approximately −30°C., or also in an organic solvent such as tetrahydrofuran ordichloroethane, but ethyl ether or isopropyl ether can also be used.

The operation is carried out in the presence of a tertiary base such astriethylamine or also pyridine or methylethylpyridine.

The optional reactive functions which are optionally protected, can bein particular the hydroxy functions. To protect these functions standardprotective groups are used such as indicated above. For example thefollowing radicals can be mentioned in a non-exhaustive manner:tetrahydropyrannyl, trimethylsilyl, triphenylmethyl or tert-butyldimethylsilyl or also the protective groups known in the chemistry ofthe peptides as indicated for example in the French Patent BF 2,499,995whose content is incorporated here by reference.

In the product of formula (III), R₄ and R₅ can form a cyclic radicalwith the carbon atom which carries them such as in particular acyclohexyl radical.

The optional elimination reactions of the protective groups are carriedout according to the usual methods known to a man skilled in the art or,for example, as indicated in the Patent BF 2,499,995. The preferredmethod of elimination is acid hydrolysis using acids chosen fromhydrochloric, benzene sulphonic or para toluene sulphonic, formic ortrifluoroacetic acid. Hydrochloric acid is preferred.

The optional hydrolysis reaction of the >C═NH group into the carbonylgroup in order to convert in particular the product of formula (IV) intothe product of formula (V) is preferably carried out using an acid suchas aqueous hydrochloric acid, for example under reflux.

The action on the products of formula (VI) of the reagent of formulaHal-R′₃ in order to obtain the products of formula (V) is carried out inthe presence of a strong base such as sodium or potassium hydride. Theoperation can be carried out by phase transfer reaction in the presenceof quaternary ammonium salts such as tetrabutyl ammoniumdihydrogenphosphate salts.

The conversion of the OH radical into a halogen radical of the productsof formula (VII) in order to obtain the products of formula (X) can becarried out under the usual conditions known to a man skilled in the artsuch as in particular in a solvent such as for example tetrahydrofuranand the action of a halogenated derivative such as in particular, whenthe halogen atom is a fluorine atom, diethylaminotrifluorosulphide(DAST).

Triflic anhydride can also be reacted beforehand in order to obtain thecorresponding triflate which is then exchanged with the correspondingfluoride as is described hereafter in the examples and in particular bythe action of tetrabutylammonium fluoride.

When the halogen atom is a bromine, chlorine or iodine atom, theoperation can be carried out according to the usual conditions known toa man skilled in the art such as in particular by the action, in thepresence of triphenylphosphine, of the corresponding halogenating agentsuch as for example carbon tetrabromide, carbon tetrachloride or alsoiodine.

Conversion reactions of the OH radical of the product of formula (VII)in order to obtain the products of formulae (IX) and (XI) as definedabove in which R₃ has the meaning indicated above, are given, by way ofexample and in a non-exhaustive manner, in the preparations of Examples1 to 4 described hereafter.

The optional esterification of the free OH radical is carried out understandard conditions. An acid or a functional derivative can for examplebe used, for example an anhydride such as acetic anhydride in thepresence of a base such as pyridine.

The optional esterification, salification or amidification of the COOHradical is carried out under standard conditions known to a man skilledin the art such as, for example, for amidification, the use of a primaryor secondary amine on a functional derivative of the acid for example asymmetrical or mixed anhydride.

Also a subject of the present invention is a preparation process for theproducts of formula (I′):

in which X, Y, R′₁, R′₂, R′₃, R₄ and R₅ are as defined above, processcharacterized in that a product of formula (P1):

in which R′₁ and R′₂ have the previous meanings and Hal represents ahalogen atom, is reacted with a product of formula (P2):

in which X, Y, R′₃, R₄ and R₅ have the meanings indicated above, thereaction being carried out in the presence of a catalyst and optionallyof a solvent.

With regard to the products of formula (P2), the term Hal preferablydesignates the chlorine atom, but can also represent a bromine or iodineatom.

The reaction conditions of such a process are in particular thosedescribed in EP 0494819.

The products which are a subject of the present invention have usefulpharmacological properties, in particular they fix on the androgenreceptors and′they present an anti-androgen activity.

Tests given in the experimental part illustrate these properties.

These properties make the products of formula (I) as defined above ofthe present invention of use as medicaments mainly for:

the treatment of adenomas and neoplasias of the prostate as well asbenign hypertrophy of the prostate, on its own or in combination withanalogues of LHRH. They can also be used in the treatment of benign ormalignant tumours possessing androgen receptors and more particularlycancers of the breast, the skin, the ovaries, the bladder, the lymphaticsystem, the kidney and the liver,

the treatment of cutaneous affections such as acne, hyperseborrhea,alopecia or hirsutism. These products can therefore be used on their ownin dermatology or in combination with antibiotics such as thederivatives of azelaic and fusidic acids, erythromycin, as well asderivatives of retinoic acid or an inhibitor of 5 alpha-reductase suchas (5 alpha,17 beta)-1,1-dimethylethyl 3-oxo 4-aza-androst-1-ene17-carboxamide (or Finasteride, Merck 11th Ed.) for the treatment ofacne, alopecia or hirsutism. They can also be combined with a productstimulating hair growth such as Minoxidil for the treatment of alopecia.

The products of formula (I), as defined above, in radioactive form(tritium, carbon 14, iodine 125 or fluorine 18) can also be used asspecific labels for the androgen receptors. They can also be used indiagnostics using medical imagery.

The products of formula (I) as defined above can also be used in theveterinary domain for the treatment of behavioural disorders such asaggressiveness, androgen-dependent affections, such as circum analum indogs and tumours having androgen receptors. They can also be used tobring about a chemical castration in animals.

Therefore a subject of the invention is the use, as medicaments, of theproducts of formula (I) as defined above, said products of formula (I)being in all the possible racemic or optically-active isomer forms, aswell as the addition salts with pharmaceutically acceptable mineral ororganic acids or mineral and organic bases of said products of formula(I).

A particular subject of the invention is the products of formula (I) asdefined above, in which:

R₁ and R₂ represent a cyano radical and a trifluoromethyl radical,

R₃ represents a linear or branched alkyl, alkenyl or alkynyl radicalcontaining at most 4 carbon atoms substituted by a radical chosen fromthe nitrooxo and

radicals in which R₉ represents a hydrogen atom, a linear or branchedalkyl radical containing at most 4 carbon atoms or a cycloalkyl radicalcontaining 5 or 6 members,

R₄ and R₅ either are identical or different and represent a methylradical optionally substituted by a fluorine atom, or form with thecarbon atom to which they are attached a cyclohexyl radical

X and Y represent an oxygen atom, said products of formula (I) being inall the possible racemic, enantiomeric and diastereoisomeric isomerforms, as well as the addition salts with pharmaceutically acceptablemineral and organic acids or mineral and organic bases of said productsof formula (I).

A subject of the invention is also the use, as medicaments, of thefollowing products:

4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-2,4-dioxo-1-imidazolidinyl)butyl and 1-methylethylcarbonate,

4-(4,4-dimethyl-2,5-dioxo-3-(4-nitrooxybutyl)-1-imidazolidinyl)-2-(trifluoromethyl)benzonitrile,said products of formula (I) being in all the possible racemic,enantiomeric and diastereoisomeric isomer forms, as well as the additionsalts with pharmaceutically acceptable mineral and organic acids ormineral and organic bases of said products of formula (I).

The products can be administered by parenteral, buccal, perlingual,rectal or topical route.

A subject of the invention is also the pharmaceutical compositions,characterized in that they contain, as active ingredient, at least oneof the medicaments of formula (I), as defined above.

These compositions can be presented in the form of injectable solutionsor suspensions, tablets, coated tablets, capsules, syrups,suppositories, creams, ointments and lotions. These pharmaceutical formsare prepared according to the usual methods. The active ingredient canbe incorporated with excipients usually employed in these compositions,such as aqueous or non-aqueous vehicles, talc, gum arabic, lactose,starch, magnesium stearate, cocoa butter, fatty substances of animal orvegetable origin, paraffin derivatives, glycols, various wetting,dispersing or emulsifying agents, preservatives.

The usual dose, variable according to the subject treated and theaffection in question, can be, for example, from 10 mg to 500 mg per dayfor man, by oral route.

The products of formula (II) used at the start of the invention can beobtained by the action of phosgene when X represents an oxygen atom orthiophosgene when X represents a sulphur atom on the corresponding amineof formula (A):

in which R′₁ and R′₂ have the meanings indicated above.

A product of this type is described in particular in the French PatentBF 2,329,276.

Amines of formula (A) are described in the European Patent EP 0,002,892or the French Patent BF 2,142,804.

The products of formula (III) are known or can be prepared from thecorresponding cyanhydrin according to the process described in thepublications: J. Am. Chem. Soc. (1953), 75, 4841, BEIL I 4 526 or J.Org. Chem. 27 2901 (1962).

The products of formula (III) can also be obtained by the action of aproduct of formula R′₃ Hal on 2-cyano 2-amino propane. A preparationexample of this type is described in the reference:

Jilek et al. Collect. Czech. Chem. Comm. 54(8) 2248 (1989).

The starting products of formulae (P1), (P2) and (VIII) as defined aboveare known and commercially available or can be prepared according to themethods known to a man skilled in the art.

The compound of formula (VIII) can in particular be an alkyl orcycloalkyl chloroformate, as is indicated in the preparation of Examples1 to 3.

The preparation of products of formula (P2) is described in particularin the following publications:

Zhur. Preklad. Khim. 28, 969-75 (1955) (CA 50, 4881a, 1956)

Tetrahedron 43, 1753 (1987)

J. Org. Chem. 52, 2407 (1987)

Zh. Org. Khim. 21, 2006 (1985)

J. Fluor. Chem. 17, 345 (1981)

or in the Patents:

German DRP 637,318 (1935)

European EP 0,130,875

Japanese JP 81,121,524.

The products of formula (P2) which are derivatives of hydantoin arewidely used and mentioned in the literature such as for example in thefollowing articles:

J. Pharm. Pharmacol., 67, Vol. 19(4), p. 209-16 (1967)

Khim. Farm. Zh., 67, Vol. 1 (5) p. 51-2

German Patent 2,217,914

European Patent 0,091,596

J. Chem. Soc. Perkin. Trans. 1, p. 219-21 (1974).

The starting products of formulae (VI) and (VII) can be prepared inparticular as indicated in the Patent Applications EP 0494819 or EP0580459.

A subject of the invention is also, as new industrial products and inparticular as new industrial products of use as intermediates for thepreparation of products of formula (I) as defined above, the products offormulae (IV) and (V) as defined above.

A subject of the present invention is also the use of the products offormula (I) as defined above, for the preparation of pharmaceuticalcompositions intended for the treatment of adenomas and neoplasias ofthe prostate as well as of benign hypertrophy of the prostate, on theirown or in combination with analogues of LHRH, for the treatment ofcutaneous affections such as acne, hyperseborrhea, alopecia or hirsutismor in diagnostics using medical imagery.

A particular subject of the present invention is the use of the productsof formula (I) as defined above, in which R₃ represents a radicalsubstituted by the nitrooxy radical, for the preparation ofpharmaceutical compositions intended for the treatment of cutaneousaffections such as acne, alopecia or hirsutism.

The following examples illustrate the invention without however limitingit.

EXAMPLE 14-(3-(4-cyano-3-(trifluoromethyl)-phenyl)-5,5-dimethyl-2,4-dioxo-1-imidazolidinyl)butyland 1-methylethyl carbonate

0.369 g of4-(4,4-dimethyl-2,5-dioxo-3-(4-hydroxybutyl)-1-imidazolidinyl)-2-(trifluoromethyl)-benzonitrileobtained in Example 1 of EP 0,580,459 and 24 ml of dimethylaminopyridinein solution in 3.5 mg of pyridine dried over potash are introduced, thewhole is cooled down to 0° C. and 2 ml of a toluenic solution of 1 Misopropyl chloroformate is added. After 2 hours 15 minutes of agitation,the reaction medium is poured into 30 g of water+ice and extracted withether. The ethereal phases are combined, washed with a saturatedsolution of sodium chloride and dried. The oil obtained is taken up intoluene and evaporation to dryness is carried out under reducedpressure. After chromatography on silica, eluting with methylenechloride—ethyl acetate: 100-3, 0.413 g of expected product (whitecrystals) is obtained. M.p.=82° C.

ANALYSES

Microanalysis for C₂₁H₂₄F₃N₃O₅: 455.44

C % H % F % N % calculated 55.38 5.31 12.51 9.23 found 55.4  5.2  12.7 9.2 

EXAMPLE 2 4-[3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-2,4-dioxo-1-imidazolidinyl] butyl and cyclohexylcarbonate

The operation is carried out as in Example 1, starting with 740 mg of4-(4,4-dimethyl-2,5-dioxo-3-(4-hydroxybutyl)-1-imidazolidinyl)-2-(trifluoromethyl)-benzonitrileobtained in Example 1 of EP 0,580,459, 48 mg of 4-dimethylaminopyridineand 7 ml of pyridine, the whole is cooled down to 10° C.±2° C. and 650mg of cyclohexyl chloroformate is added. The operation is continued asin Example 1 and after chromatography on silica, eluting with methylenechloride—ethyl acetate: 97-3, 948 mg of expected product is obtained.

M.p.=121-122° C.

ANALYSES

Microanalysis for C₂₄H₂₈F₃N₃O₅: 495.5

C % H % F % N % calculated 58.18 5.70 11.50 8.48 found 58.2  5.8  11.3 8.4 

EXAMPLE 3 4-[3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-2,4-dioxo-1-imidazolidinyl] butyl and cyclopentylcarbonate

The operation is carried out as in Example 2, starting with 740 mg of4-(4,4-dimethyl-2,5-dioxo-3-(4-hydroxybutyl)-1-imidazolidinyl)-2-(trifluoromethyl)-benzonitrileobtained in Example 1 of EP 0,580,459, 48 mg of 4-dimethylaminopyridineand 7 ml of pyridine, the whole is cooled down in an ice bath and 600 mgof cyclopentyl chloroformate is added. By proceeding as in Example 2,904 mg of expected product (white crystals) is obtained. M.p.=81-82° C.

ANALYSES

Microanalysis for C₂₃H₂₆F₃N₃O₅: 481.47

C % H % F % N % calculated 57.37 5.44 11.84 8.73 found 57.5  5.4  11.7 8.7 

EXAMPLE 4 4-(4,4-dimethyl-2,5-dioxo-3-(4-nitrooxybutyl)-1imidazolidinyl)-2-(trifluoromethyl)-benzonitrile

STAGE 1:4-(4,4-dimethyl-2,5-dioxo-3-(4-iodobutyl)-1-imidazolidinyl)-2-(trifluoromethyl)-benzonitrile

787 mg of triphenyl phosphine, 204 mg of imidazole, 762 mg of iodine and5 ml of methylene chloride are introduced, the suspension is agitatedfor 45 minutes at ambient temperature, then over about 3 minutes, 1.1 gof4-(4,4-dimethyl-2,5-dioxo-3-(4-hydroxybutyl)-1-imidazolidinyl)-2-(trifluoromethyl)-benzonitrileobtained in Example 1 of EP 0,580,459 in 7 ml of methylene chloride isadded. Rinsing is carried out with 1 ml of methylene chloride followedby agitation for 4 hours at ambient temperature.

The insoluble part is separated off, rinsed with methylene chloride, theorganic phase is washed with a saturated aqueous solution of sodiumthiosulphate then with salt water and dried. Chromatography is carriedout on silica eluting with methylene chloride—ethyl acetate: 97-3. Aftercrystallization from ether, 1.26 g of expected product (white crystals)is obtained. M.p.=87-88° C.

Physical Analyses

Microanalysis for C₁₇H₁₇F₃IN₃O₂: 479.24

C % H % F % I % N % calculated 42.61 3.57 11.89 26.48 8.77 found 42.7 3.3  11.9  26.2  8.5 

STAGE 2:4-(4,4-dimethyl-2,5-dioxo-3-(4-nitrooxybutyl)-1imidazolidinyl)-2-(trifluoromethyl)-benzonitrile

1 g of the product obtained in Stage 1 above, is introduced into 10 mlof acetonitrile and 426 mg of silver nitrate is added to the solutionobtained. The reaction medium is left to react 16 hours at ambienttemperature, the insoluble part is separated off, rinsed twice withmethylene chloride and evaporated. After purification by chromatographyon silica eluting with methylene chloride—ethyl acetate: 99-1, 845 mg ofexpected product (white crystals) is obtained. M.p.=74-75° C.

Physical Analyses

Microanalysis for C₁₇H₁₇F₃N₄O₅: 414.34

C % H % F % N % calculated 49.28 4.13 13.75 13.52 found 49.2  4.0  13.7 13.5 

EXAMPLE 5

Tablets were prepared having the following composition:

Product of Example 1 . . . 100 mg

Excipient s.q. for a tablet made up to . . . 300 mg

(Detail of the excipient: lactose, starch, talc, magnesium stearate).

PHARMACOLOGICAL STUDY OF THE PRODUCTS OF THE INVENTION 1) Study of theAffinity of the Products of the Invention for the Androgen Receptor

Male Sprague Dawley EOPS rats weighing 180-200 g, castrated 24 hourspreviously, are sacrificed, the prostates are removed, weighed andhomogenized at 0° C. using a potter glass flask, in a buffered solution(10 mM Tris, 0.25M saccharose, 0.1 mM PMSF(phenylmethanesulphonylfluoride), 20 mM sodium molybdate, HCl pH 7.4; towhich 2 mM of DTT (DL dithiothreitol) is added extemporaneously), at therate of 1 g of tissue per 8 ml of buffer.

The homogenate is then ultracentrifuged at 0° C., for 30 minutes at209,000 g. The aliquots of the supernatant obtained (=cytosol), areincubated for 30 minutes and for 24 hours at 0° C., with a constantconcentration (T) of tritiated testosterone and in the presence ofincreasing concentrations (0 to 2500×10⁻⁹M), either of unlabelledtestosterone, or of the products to be tested. The concentration ofbound tritiated testosterone (B) is then measured in each incubate bythe method of adsorption on carbon-dextran.

Calculation of the Relative Bond Affinity (RBA)

The following 2 curves are drawn: the percentage of the bound tritiatedhormone B/T as a function of the logarithm of the concentration of theunlabelled reference hormone and B/T as a function of the logarithm ofthe concentration of unlabelled tested product. The straight line of theequation

I₅₀=(B/Tmax+B/Tmin)/2.

B/T max=of the bound tritiated hormone for an incubation of thistritiated hormone at the concentration (T).

B/T min=% of the bound tritiated hormone for an incubation of thistritiated hormone at the concentration (T) in the presence of a largeexcess of unlabelled hormone (2500×10⁻⁹M).

The intersections of the straight line I₅₀ and the curves, allow theevaluation of the concentrations of theunlabelled reference hormone (CH)and of the tested unlabelled product (CX) which inhibit by 50% thebindingof the tritiated hormone on the receptor. The relative bondaffinity (RBA) of the tested product is determined by the equationRBA=100 (CH)/(CX).

The following results are obtained, expressed in RBA.

Reference product (testosterone): 100

TABLE 1 Product of example RBA: Incubation for 24 hours 1 19

2) Determination of the Reducing Effect on the Costo-vertebral Gland ofthe Hamster

The local activity (topical) of an antiandrogen is determined by thereduction which it produces in the surface area of the costovertebralgland of the hamster (hereafter C.V.G.), an androgen-dependent organsituated on the sides of the animal.

The animals are male hamsters weighing approximately 140 g, 14 weeks oldand originating from the Charles Riverbreed (USA), they are subjected toa long photoperiod (16 hours of light, 8 hours of darkness). The animalsare treated every day, except for the weekend, for 3 weeks (14administrations). The product to be tested is applied, by topical route,to the right-hand G.C.V., the left-hand one serving as the control, thesurface of the gland having been shaved beforehand. The animals aresacrificed by bleeding the carotid artery 24 hours after the lasttreatment. The C.V.G.'s are removed, measured and weighed. The localactivity of a product is determined by the % reduction in the surfacearea of the C.V.G. which it induces in comparison with the 1st of daythe experiment and compared to the animals treated with solvent only.

TABLE 2 Product of example % CVG reduction with 3 μg/jour 1 −32

3) Determination of the Reducing Effect in the Weight of the Prostate inan Intact Male Rat

The systemic activity of an antiandrogen is determined by the reductionin the weight of the prostate which it produces in an intact animal.

The animals used are male rats of the Sprague Dawley strain weighingapproximately 200 g, 7 weeks old, originating from the Iffa Credo breed(France). The experiment is carried out over two weeks, except for theweekend.

The product can be administered by oral, sub-cutaneous or percutaneousroute.

The solvents used are then:

by oral route: 0.5% aqueous solution of methylcellulose under a volumeof 5 ml/kg,

by sub-cutaneous route: wheatgerm oil in 10% ethanol under a volume of0.2 ml/kg,

and by percutaneous route: ethanol under a volume of 50 μl on thepreviously-shaved skin.

The treatment is carried out from day 0 to day 4 then (after theweekend) from day 7 to day 10. The animals are sacrificed the day afterthe last treatment by bleeding the carotid artery, the prostates areremoved and fixed in demineralized water containing 10% formol for 72hours. They are then dissected and weighed. The blood is removed inorder to determine, by radioimmunological assay, the amount of serictestosterone. The anti-androgen activity of the product is expressed in% reduction in the weight of the prostates and in % variation in theamounts of testosterone compared to the animals treated with the solventonly.

TABLE 3 % réduction in the prostate Product of example weight with 3mg/kg P.O. 1 −5

What is claimed is:
 1. A compound selected from the group consisting ofa compound of the formula

wherein R₁ and R₂ are individually selected from the group consisting of—CN, and —CF₃, R₃ is selected from the group consisting of alkyl,alkenyl and alkynyl, all of up to 4 carbon atoms and substituted with amember selected from the group consisting of nitrooxy and

R₉ is alkoxy of 1 to 4 carbon atoms or cycloalkyloxy of 5 to 6 carbonatoms, R₄ and R₅ are individually methyl unsubstituted or substituted byfluorine or taken together with the carbon atom to which they areattached form cyclohexyl, X and Y are oxygen in all racemic,enantiomeric and diasostereo isomeric forms thereof and its salts of anon-toxic, pharmaceutically acceptable base and acid.
 2. A compoundhaving the formula

X is oxygen or sulfur, R′₁, R′₂, R′₃ and R′₄ have the definition of R₁,R₂, R₃ and R₄ in claim 1 with any reactive groups unprotected orprotected and R₄ and R₅ are as defined in claim
 1. 3. An antiandrogeniccomposition comprising an antiandrogenically effective amount of acompound selected from the group consisting of4-(3-(4-cyano-3-trifluoromethyl-phenyl)-5,5-dimethyl-2,4-dioxo-1-imidazolidinyl)-butyland isopropyl carbonate and4-(4,4-dimethyl-2,5-dioxo-3-(4-nitrooxybutyl)-1-imidazolidinyl-2-trifluoromethyl-benzonitrile.4. A compound of claim 1 selected from the group consisting of4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-2,4-dioxo-1-imidazolidinyl)butyl and 1-methylethylcarbonate, 4-(4,4-dimethyl-2,5-dioxo-3-(4-nitrooxybutyl)-1imidazolidinyl)-2-(trifluoromethyl) benzonitrile, said products offormula (I) being in all the possible racemic, enantiomeric anddiastereoisomeric isomer forms, or the addition salts with mineral andorganic acids or with mineral and organic bases of said products offormula (I).
 5. A method of inducing antiandrogenic activity in a warmblooded animal comprising administering to warm-blooded animals anantiandrogenically effective amount of a compound of claim
 1. 6. Themethod of claim 5, wherein the compound is selected from the groupconsisting of 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-2,4-dioxo-1-imidazolidinyl)butyl and 1-methylethylcarbonate, 4-(4,4-dimethyl-2,5-dioxo-3-(4-nitrooxybutyl)-1imidazolidinyl)-2-(trifluoromethyl) benzonitrile.